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Hepatic drug transporters and nuclear receptors:Regulation by therapeutic agents

World Journal of Gastroenterology 2008年第46期14卷 7068-7074页

作者： aldo d mottino Viviana A Catania Instituto de Fisiología Experimental Facultad de Ciencias Bioquímicas y FarmacéuticasUniversidad Nacional de RosarioSuipacha 570(S2002LRL)-RosarioArgentina

The canalicular membrane represents the excretory pole of *** is an important route of elimination of potentially toxic endo-and xenobiotics(including drugs and toxins),mediated by the major canalicular transporters:multidrug resistance protein 1(MdR1, ABCB1),also known as P-glycoprotein,multidrug resistance-associated protein 2(MRP2,ABCC2),and the breast cancer resistance protein(BCRP,ABCG2).Their activities depend on regulation of expression and proper localization at the canalicular membrane,as regulated by transcriptional and post-transcriptional events,*** transcriptional level,specific nuclear receptors(NR)s modulated by ligands,co-activators and co-repressors,mediate the physiological requirements of these *** complex system is also responsible for alterations occurring in specific liver *** briefly describe the major ClassⅡNRs, pregnane X receptor(PXR)and constitutive androstane receptor(CAR),and their role in regulating expression of multidrug resistance *** therapeutic agents regulate the expression of relevant drug transporters through activation/inactivation of these *** provide some representative examples of the action of therapeutic agents modulating liver drug transporters, which in addition,involve CAR or PXR as mediators.

关键词： drug transport Biliary secretion ABC proteins Multidrug resistance proteins Nuclear receptors Constitutive androstane receptor Pregnane X receptor Therapeutic agents

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dynamic localization of hepatocellular transporters in health and disease

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World Journal of Gastroenterology 2008年第44期14卷 6786-6801页

作者： Marcelo G Roma Fernando A Crocenzi aldo d mottino Instituto de Fisiología Experimental (IFISE)-Facultad de Ciencias Bioquímicasy Farmacéuticas (CONICET-U.N.R.) S2002LRLRosarioArgentina

Vesicle-based traffi cking of hepatocellular transporters involves delivery of the newly-synthesized carriers from the rough endoplasmic reticulum to either the plasma membrane domain or to an endosomal,submembrane compartment,followed by exocytic targeting to the plasma membrane. Once delivered to the plasma membrane,the transporters usually undergo recycling between the plasma membrane and the endosomal compartment,which usually serves as a reservoir of pre-existing transporters available on demand. The balance between exocytic targeting and endocytic internalization from/to this recycling compartment is therefore a chief determinant of the overall capability of the liver epithelium to secrete bile and to detoxify endo and xenobiotics. Hence,it is a highly regulated process. Impaired regulation of this balance may lead to abnormal localization of these transporters,which results in bile secretory failure due to endocytic internalization of key transporters involved in bile formation. This occurs in several experimental models of hepatocellular cholestasis,and in most human cholestatic liver diseases. This review describes the molecular bases involved in the biology of the dynamic localization of hepatocellular transporters and its regulation,with a focus on the involvement of signaling pathways in this process. Their alterations in different experimental models of cholestasis and in human cholestatic liver disease are reviewed. In addition,the causes explaining the pathological condition (e.g. disorganization of actin or actin-transporter linkers) and the mediators involved (e.g. activation of cholestatic signaling transduction pathways) are also discussed. Finally,several experimental therapeutic approaches based upon the administration of compounds known to stimulate exocytic insertion of canalicular transporters (e.g. cAMP,tauroursodeoxycholate) are described.

关键词： Hepatocellular transporters Cholestasis cAMP Bile salts Vesicular trafficking Endocytosis Signaling pathways

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